Immune nephritis afflicts both native and transplanted kidneys and is a leading cause of chronic renal disease. Nephritis occurs in up to 74% of patients with systemic lupus erythematosus, one of the most debilitating of the autoinflammatory diseases. Insights into disease pathogenesis are emerging from the complementary study of human and mouse lupus, although rapid progress has been hindered by the extensive clinical heterogeneity and genetic complexity of this disease. This proposal uses a new model system developed over the past five years to track discrete autoimmune cell populations within the context of distinct constellations of lupus susceptibility genes. Extensive preliminary studies reveal that each of the four classic lupus strains, NZB, BWF1, BXSB, and MRL/lpr, modified to express the identical nephritis-associated receptor, displays a unique tolerance phenotype. The goal of this proposal is to dissect the molecular mechanisms regulating autoimmunity that destroys kidneys. This effort relies on cutting edge but validated technologies and cross-disciplinary collaboration. Specific Aim 1 will use in vitro and in vivo approaches to identify the cellular and molecular basis of altered tolerance revealed in NZB, a strain that develops hematologic and renal disease and contributes major susceptibility loci to fulminant nephritis. Specific Aim 2 will use existing subinterval congenics and genome mapping to localize functional genetic variants that determine the defective tolerance phenotype. Specific Aim 3 will dissect the cellular, molecular, and genetic basis of altered tolerance in the setting of accelerated lupus nephritis, including determining the basis of the unique hyperproliferation and marginal zone-like phenotype in BXSB. Collectively, these strains model the genetic heterogeneity of human lupus, and their study should ultimately provide insight into regulatory and disease mechanisms applicable to patients.